Project Summary/Abstract This proposal brings together a top team with diverse and complementary expertise to develop a novel therapeutic agent based on a newly described serum protein, renalase (RNLS) to treat acute pancreatitis (AP). This protein appears to have a novel protective effect in models of acute tissue injury, including AP. AP affects more than 250,000 people/year in the USA and can cause death in 30% of those with severe disease. It is the most common reason for hospitalization in the USA for individuals with gastrointestinal disease. RNLS is produced in the kidneys and other tissues including the pancreas. Initial data show that: 1) Serum RNLS rapidly decreases soon after the onset of AP in a murine model and in humans; 2) Genetic deletion of RNLS increases the severity of experimental acute murine pancreatitis; 3) Recombinant RNLS (rRNLS) reduces pancreatitis responses in isolated murine pancreatic acinar cells; 4) Exogenous rRNLS significantly reduces the severity of acute murine pancreatitis in vivo when given either as pretreatment or two hours after the onset of disease. Initial studies show that RNLS-derived peptides reduce acute injury in several types of cultured cells. This protective effect has been localized to the C-terminal region of RNLS. These findings suggest that RNLS will have a protective role in AP. The proposed studies will examine RNLS-derived peptides and compare their potency to rRNLS in reducing AP injury. The peptides may have advantages over rRNLS by way of ease of manufacture and stronger patent position. Lead drugs will be selected and examined with the following Specific Aims: 1) RNLS and RNLS-derived, smaller peptides will be compared/prioritized for their potency in reducing pancreatitis responses in isolated murine pancreatic acinar cells. 2) The effects on AP severity of rRNLS and the two most potent peptides identified in Aim 1 will be examined in two experimental murine models: a mild form of AP induced by high doses of cerulein and a severe model of AP induced by intraperitoneal alcohol and a fatty acid. To further reflect clinical treatment scenarios, the effectiveness of rRNLS or related peptides will be examined when given prior to the onset of injury or after the onset of disease. Further, traditional biochemical measures of AP will be correlated with RNLS levels as well as pain, a key symptom of acute pancreatitis. With success the project will be poised for late stage development and clinical studies of a novel and rationally designed therapeutic. Based on the strength of the preliminary data and evidence that this novel survival pathway is fundamentally important in both murine models and human disease, RNLS therapy has a very high potential for being effective in preventing or treating AP.